It has been estimated that approximately 9% of the United States adult population suffers from moderate to severe non-cancer-related chronic pain (American Academy of Pain Medicine, 2001). Chronic pain, which can be defined as pain lasting longer than one month (Bonica, Semin Anesth 1986, 5:82-99), can be described as unrelenting persistent pain that is not amenable to routine pain control methods. As many as 90 million Americans may have suffered from chronic pain, and of these, up to 60 million may have been either partially or totally disabled for periods ranging from a few days to years (Bonica, Semin Anesth 1986, 5:82-99).
Chronic pain states may be classified in several ways. One broad classification distinguishes somatogenic pains, those explicable in terms of physiologic mechanisms, from psychogenic pains, those better understood in psychological terms. A related taxonomy attempts to further distinguish pains by their presumed pathogenesis. For example, nociceptive pain is due to activation of pain-sensitive nerve fibers, either somatic or visceral. When somatic nerves are involved, the pain is typically experienced as aching or pressure-like. Deafferentation pain is due to nerve tissue damage that results in interruption of afferent pathways and can be further differentiated on the basis of response to sympathetic nerve blockade. Finally, psychogenic pains are those due to psychologic source and are not nociceptive or neuropathic.
Pain of long duration loses its adaptive biologic role. Vegetative signs gradually develop, e.g., lassitude, sleep disturbance, decreased appetite, loss of taste for food, weight loss, diminished libido, and constipation. A depressed affect may predominate. Notably, in many patients, the psychological impairment is more disruptive to their life than the continued perception of pain.
The prevalence of chronic pain is particularly high in specific populations, such as the elderly (Mobily, J Aging Health 1994, 6:139-154; Crook et al., Pain 1984, 18:299-314) and post surgical patients (Crook et al., Pain 1984, 18:299-314; Perttunen et al., Acta Anaesthesiol Scand 1999, 43:563-567; Callesen et al., Br J Surg 1999, 86:1528-1531). Among the elderly, it has been estimated that of those who live in the community, 25% to 50% suffer from pain, and of those living in nursing homes, 49% to 83% suffer from pain that interferes with activities of daily living (Ferrel and Ferrell, Compr Ther 1991, 17:53-58; Ferrell, Ann Ther Med 1995, 123:681-687).
A wide range of agents (e.g., nonsteroidal anti-inflammatory drugs, acetaminophen) can be used for the treatment of chronic pain in the elderly and other populations (Brusso and Brose, Ann Rev. Med, 1998, 49:123-133), but opioids remain an important source of pharmacotherapy for this condition (Chemy, J. Oncol Manag 2000, 9:8-15). Opioids may be administered in a variety of dosage forms, including controlled transdermal delivery, which has the potential to increase the convenience of opioid therapy and reduce some of the potential side effects (Ahmedzai, Eur. J. Cancer 1997, 33:58-514; Jeal and Benfield, Drugs 1997, 53:109-138; Mercadente, Cancer 1999, 86:1856-66). Advantages of this approach include application once every several days and avoidance of high peak plasma drug concentrations that may result in adverse events, such as orthostatic hypotension (Dayer et al., Drugs 1997, 53:18-24; Merecadante and Fulfaro, Oncology 1999, 13:215-220, 225).
Transdermal delivery systems in which an opioid analgesic is the active ingredient are commercially available, including, for example, Duragesic for the administration of fentanyl. The Duragesic patch purportedly provides adequate analgesia for up to 48 to 72 hours (2 to 3 days).
In the treatment of the elderly with transdermal dosage forms, the marked changes in the skin of the elderly versus younger individuals should be considered. For example, the thickness of the skin is reduced in the elderly, and sebum secretion is decreased (Seindenari et al., Skin Pharmacol 1994, 7:201-209; Jacobsen et al., J Invest Dermatol 1985, 85:483-485); The number of collagen fibers in the skin declines in old age (Lovell e t al., Br J Dermatol 1987, 117:419-428; Moragas et al., Analyt Quant Cytol Histol 1998, 20:493-499); and the blood flow to the skin is decreased (Rooke et al., J Appl Physiol 1994, 77:11-14; Weiss et al, Age Ageing 1992, 21:237-241).
Buprenorphine is a potent, partial agonist of the μ-opioid receptor that has been shown to be effective to control pain in a wide range of patients when delivered by a number of different routes of administration, including intravenously, epidurally, intrathecally, or sublingually in both young and elderly patients (Inagaki et al., Anesth Analg 1996, 83:530-536; Brema et al., Int J Clin Pharmacol Res 1996, 16:109-116; Capogna et al., Anaesthesia 1988, 43:128-130; Adrianensen et al., Acta Anaesthesiol Belg 1985, 36:33-40; Tauzin-Fin et al., Eur J Anaesthesiol 1998, 15:147-152; Nasar et al., Curr Med Res Opin 1986, 10:251-255). There are several types of transdermal formulations of buprenorphine reported in the literature. See, for example, U.S. Pat. No. 5,240,711 to Hille et al., U.S. Pat. No. 5,225,199 to Hidaka et al., U.S. Pat. No. 5,069,909 to Sharma et al., U.S. Pat. No. 4,806,341 to Chien et al.; U.S. Pat. No. 5,026,556 to Drust et al.; U.S. Pat. No. 5,613,958 to Kochinke et al.; and U.S. Pat. No. 5,968,547 to Reder et al. Transdermal delivery systems of buprenorphine, made by Lohmann Therapie-Systeme GmbH & Co., are currently sold in the European Union under the trademark name TRANSTEC®. These patches contain 20, 30, and 40 mg of buprenorphine, with an approximate delivery or “flux” rate of 35, 52.5, and 70 μg/hr, respectively. The current buprenorphine transdermal systems, however are prescribed for a 7-day dosage period. This may take weeks for a patient in need of an escalated dose to reach a level where the pain relief is effective.
Chronic pain is also a significant problem in the pediatric population, and the physical and psychological symptoms associated with chronic pain may impact overall health and predispose for development of adult chronic pain. In children, chronic pain can be caused by a variety of medical conditions, including juvenile arthritis, cerebral palsy, scoliosis, postoperative, and cancer.
Adolescent and juvenile scoliosis is a spinal abnormality characterized by a lateral curvature in the coronal plane. Techniques for pain management after spinal surgery include intravenous injections, oral medication, patient controlled analgesic delivery systems, and epidural catheter drug delivery. Generally, patients are on a combination of these treatments for 2-4 days after surgery, following which oral analgesics are typically sufficient. However, pain medications may be needed for up to three months after surgery to control residual pain.
Juvenile arthritis (JA) refers to chronic arthritic conditions affecting a pediatric patient, usually under the age of 16 years and often associated with chronic pain. JA covers different conditions where joint inflammation is the major manifestation, further characterized by cycles of flare ups and remissions. Current therapies include treatments to reduce swelling; maintain full movement in the affected joints; relieve pain; and identify, treat, and prevent complications. Medications currently in use include nonsteroidal anti-inflammatory agents (such as ibuprofen and naproxen), methotrexate, sulfasalazine, penicillamine, and hydroxychloroquine. Oral steroid medications are effective, but have adverse side effects with long-term use. Steroid injections into the affected joints may also be effective, however the mode of delivery is often problematic for children. New anti-inflammatory monoclonal antibodies, such as Enbrel, have provided intermittent relief for many treatment resistant patients.
Cerebral palsy is a collective name given to a range of conditions of unknown etiology. For pediatric patients with cerebral palsy, management and prevention of muscle spasm is a common goal. Epidural analgesia is particularly valuable when major orthopedic procedures are performed (Nolan et al., Anesthesia 2000 January; 55(1):32-41). Also, continuous infusions of epidural bupivacaine and fentanyl, a cumbersome procedure, have been used to provide analgesia for children with CP without serious complications, while intermittent bolus epidural morphine was associated with a high incidence of excessive sedation (Brenn et al., Can J Anaesth 1998, 45(12):1156-61). Some of the drugs used in the management of spasms are baclofen and botulinum toxin.
In general, current medications to relieve pain in children include paracetamol, aspirin, non-steroidal anti-inflammatory compositions, opioids (both natural and synthetic) and opioid analogs. While new techniques for pain control in the pediatric population have been proposed, including opioid administration by transdermal or transmucosal absorption, and the use of neuraxial analgesia (Golianu et al., Pediatr Clin North Am 2000, 47(3):559-87), improved methods of long-term pain control are still needed.
Despite advances in the art, there remains a need for methods of effectively treating patients suffering from pain so that effective analgesic levels of buprenorphine are provided for prolonged periods of time without substantially increasing the incidence of adverse side effects, such as nausea or orthostatic hypotension. These concerns are particularly important with respect to providing a safe and effective method of pain management for at risk patients like the elderly, hypertensive patients, patients with respiratory conditions and pediatric patients.